The invention relates to an apparatus and method for the determination of concentrations of biological compounds, such as drugs and their metabolites, in vivo using microdialysis in combination with mass spectrometry.
Sepsis is a major problem in surgical critical care today. Infections, septic shock and multiple organ failure attributed to overwhelming sepsis are among the leading causes of complications, death and excessive financial burdens in tertiary surgical intensive care units. While surgical drainage and debridement techniques are often essential in control of sepsis, antibiotic infusions are usually relied upon as a cornerstone of therapy.
The development and availability of new drugs such as antibiotics and immunosuppressive agents have revolutionized the approach of modern medicine to the treatment of many conditions and diseases. The potency of many new antibiotics is extremely high and they are effective against many new resistant strains. Unfortunately, many of these drugs are also toxic to man and have deleterious effects on various organs and systems in the body. In addition, their metabolic fates can be complex, with some of the metabolites having strong physiological effects as well. This has resulted in many, if not most, critically ill patients being actually underdosed with regard to the antibiotic levels required for optimal inhibition of bacterial growth.
The determination of blood levels of these powerful new therapeutic agents and their metabolites is essential both in their clinical use and their use in the research laboratory. Methods which would allow such analyses in vivo and in real-time would be particularly advantageous in providing i) blood and/or tissue levels of patients during critical periods to maximize therapeutic value and minimize toxic effects, ii) tissue responses at specific sites in the body and in a time-course study, iii) verification of the presence and accumulation of intermediate metabolites which may have significant clinical implications, iv) improved quantification due to decreased sample handling losses and variable extraction efficiencies, and v) ease of use and time saving advantages because individual extraction, purification and derivatization steps are not required.
Modern mass spectrometric techniques, such as fast atom bombardment (FAB) mass spectrometry, offer unique analytical capabilities for quantification of drugs and their metabolites because they are effective in providing mass specific detection of compounds in complex mixtures derived from biological sources without the need for extraction and derivatization methods. However, samples for FAB analysis, for example, are typically prepared with high concentrations of glycerol or other suitable viscous liquids so that the samples remain in a liquid state during the introduction into the high vacuum chamber of the system throughout the analysis period. The presence of the added viscous liquid matrix results in several severe limitations including high background interfering solvent or matrix ion clusters, and relatively poor sensitivity.